The overall objective of this program is to develop a detailed understanding of the molecular and structural basis for the genesis and assembly of the red cell, with emphasis on the membrane skeleton. A continuing long term goal is to understand the pathophysiologic mechanisms of red cell disorders. The current proposal also reflects some broadening of research interests to develop improved understanding of erythroid differentiation and of the role of 4.1 family of proteins in the functional organization of non-erythroid cells. To achieve these broad goals, four complementary approaches are proposed: 1) Explore the molecular basis for modulation of 4.1R gene expression during erythroid differentiation and test the hypothesis that the highly homologous 4.1G protein plays an important role in erythropoiesis, and may compensate for the loss of 4.1R in 4.1R knockout mice. 2) Explore the hypothesis that regulation of diverse cellular functions by 4.1 involves protein 4.1 mediated assembly and disassembly of organelle and cell-specific supramolecular protein complexes between membrane proteins, signaling molecules and cytoskeletal proteins; and that this assembly/disassembly is regulated by 4.1 phosphorylation-dephosphorylation and by the interaction of 4.1 with anionic phospholipids. 3) Develop mechanistic understanding of chromatin condensation, movement of the nucleus to the plasma membrane and partitioning of erythroblast plasma membrane proteins between the reticulocyte and extruded nucleus at the conclusion of erythroid differentiation. 4) Examine structural changes occurring in malaria-infected red blood cells and elucidate the functional consequences of interaction between red cell membrane proteins and proteins elaborated by intraerythrocytic stages of the malarial parasite. To achieve these objectives, a group of investigators with expertise in hematology, biochemistry, cell biology, biophysics, genetics, molecular biology and structural biology, and a long standing interest in the study of membrane physiology, have come together to mount a concerted effort. It is anticipated that information gathered during these studies will contribute towards increased general understanding of the role of skeletal proteins in membrane assembly, homeostasis and structure-function relationships in erythroid cells in particular and somatic cells in general.